The long-range goal of this research is to identify the significant antigen presenting cells (APC) that induce peripheral tolerance to self antigens, with a focus on weakly autoreactive B cell subsets. B cells are particularly efficient APC for antigens bound to their antigen receptors, so self-reactive B cells may present self-antigens more efficiently than conventional tolerizing APC in the thymus and periphery. To avoid positive feedback in a vicious cycle of mutual activation by pathogenic T and B cells, it may be necessary for autoreactive B cells to induce helper T cell tolerance to those self-antigens that they recognize and present efficiently, before those T cells are activated by infections. It is known that B cell subsets differ substantially from one another in their ability to recruit T cell help and their propensity to secrete autoantibodies, but they have not been compared with regard to their ability to induce tolerance in naive CD4 T cells. Three subsets of self-reactive B cells may be particularly important as tolerogenic APC for CD4 T cells. One subset is the short-lived, anergic, immature transitional B cells that are retained in T cell areas and fail to enter the longlived B cell compartments because their antigen receptors are engaged by self-antigens. Another is the self-renewing marginal zone B cells that are selected into this special B cell subset by self antigens, and are poised for a rapid antibody response to blood-borne pathogens. The third is the self-renewing B-1 B cells that are seeded to the periphery in early development, are selected and sustained by self-antigen reactivity, and produce germline-encoded, natural and T-independent antibodies that protect against bacterial infections. The objective of this project is to determine for the first time the intrinsic efficiency of antigen presentation and tolerance induction by B cell subsets in their natural locations in the steady state in healthy lymphoid organs, using a unique transgenic animal model in which antigen presentation can be limited to B cells of certain subsets. The proposed experiments will also test whether animals deficient in particular B cell subsets are deficient in CD4 T cell tolerance to self-antigens presented by those B cells. Relevance: The failure of self-tolerance underlies autoimmune disease. This application investigates the mechanisms that maintain self-tolerance while allowing a vigorous response to infections. Understanding mechanisms of immunological tolerance may lead to new interventions for prevention or cure of autoimmune diseases, such as lupus erythematosus, rheumatoid arthritis, and diabetes. New methods to induce immunological tolerance will also have important applications in organ and tissue transplantation, gene therapy, and treatment of chronic infections.